Interim Revision Announcement

Official September 1, 2014 Cefdinir 1

. CS = concentration of the Standard solution (µg/mL)

CU = nominal concentration of cefdinir in the
Cefdinir Capsules Sample solution (µg/mL)
Acceptance criteria: 90.0%–•110.0%• (IRA 1-Sep-2014)
DEFINITION
.

Cefdinir Capsules contain NLT 90.0% and NMT 110.0% of PERFORMANCE TESTS
the labeled amount of cefdinir (C14H13N5O5S2). • DISSOLUTION 〈711〉
Medium: 50 mM phosphate buffer, pH 6.8; 900 mL
IDENTIFICATION Apparatus 2: 50 rpm
• A. ULTRAVIOLET ABSORPTION 〈197U〉 Time: 30 min
Buffer: Prepare as directed in the Assay. Detector: UV 290 nm
Standard solution: 10 µg/mL of USP Cefdinir RS in Cell length: 0.1-cm flow cell
Buffer Standard solution: 0.33 mg/mL of USP Cefdinir RS in
Sample solution: Equivalent to 10 µg/mL of cefdinir Medium
from Capsules in Buffer. Filter before use. Sample solution: Pass a portion of the solution under
Cell size: 1 cm test through a suitable filter of 0.45-µm pore size. Di-
Blank: Use the Buffer. lute with Medium to a concentration of about 0.33 mg
Acceptance criteria: Sample solution maxima and min- /mL of cefdinir.
ima occur at the same wavelengths as those in the Blank: Dissolve 1 empty Capsule in 100 mL of Medium,
Standard solution. and dilute to 900 mL. Filter if necessary.
• B. The retention time of the major peak of the Sample Analysis
solution corresponds to that of the Standard solution, as Samples: Standard solution and Sample solution
obtained in the Assay. Calculate the percentage of the labeled amount of
ASSAY cefdinir (C14H13N5O5S2) dissolved:
Result = (AU/AS) × CS × V × D × (1/L) × 100
Change to read:
AU = absorbance of the Sample solution
• PROCEDURE AS = absorbance of the Standard solution
Buffer: 10.7 g/L of dibasic sodium phosphate and CS = concentration of the Standard solution
3.4 g/L of monobasic potassium phosphate. Adjust (mg/mL)
with phosphoric acid or sodium hydroxide to a pH of V = volume of Medium, 900 mL
7.0 ± 0.05 before final dilution. D = dilution factor for the Sample solution (mL/mL)
Solution A: 7 g/L of citric acid monohydrate. Adjust L = label claim (mg/Capsule)
with phosphoric acid to a pH of 2.0 ± 0.05. Tolerances: NLT 80% (Q) of the labeled amount of
Mobile phase: Methanol, tetrahydrofuran, and Solution cefdinir (C14H13N5O5S2) is dissolved.
A (111:28:1000) • UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet the
System suitability solution: 50 µg/mL of USP Cefdinir requirements
RS and 175 µg/mL of m-hydroxybenzoic acid in Buffer IMPURITIES
Standard solution: 50 µg/mL of USP Cefdinir RS in
Buffer
Sample solution: Equivalent to 50 µg/mL of cefdinir, Change to read:
from Capsule contents (NLT 20), in Buffer
Chromatographic system • ORGANIC IMPURITIES
(See Chromatography 〈621〉, System Suitability.) Solution A: 14.2 g/L of anhydrous dibasic sodium
Mode: LC phosphate
Detector: UV 254 nm Solution B: 13.6 g/L of monobasic potassium
Column: 3.9-mm × 15-cm; 4-µm packing L1 phosphate
Flow rate: 1.4 mL/min Buffer: Combine appropriate amounts of Solution A
Injection volume: 15 µL and Solution B (about 2:1) to obtain a solution with a
System suitability pH of 7.0 ± 0.1.
Samples: System suitability solution and Standard Solution C: Dilute tetramethylammonium hydroxide
solution (10% aqueous) with water to obtain a 0.1% solution.
Suitability requirements Adjust with dilute phosphoric acid (1 in 10) to a pH of
Resolution: Greater than 3.0 between cefdinir and 5.5 ± 0.1.
m-hydroxybenzoic acid, System suitability solution Solution D: 37.2 mg/mL of edetate disodium
Tailing factor: NMT 2.0 for cefdinir, System suitabil- Solution E: To 1000 mL of Solution C add 0.4 mL of
ity solution Solution D.
Relative standard deviation: NMT 1.0% for Solution F: Acetonitrile, methanol, Solution C, and So-
cefdinir, Standard solution lution D (150: 100: 250: 0.2)
Analysis Mobile phase: See Table 1.
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of Table 1
cefdinir (C14H13N5O5S2) in the portion of Capsules
taken: Time Solution E Solution F
(min) (%) (%)
Result = (rU/rS) × (CS/CU) × 100 0 95 5
2 95 5
rU = peak response of cefdinir from the Sample
solution 22 75 25
rS = peak response of cefdinir from the Standard 32 50 50
solution 37 50 50

2014 The United States Pharmacopeial Convention All Rights Reserved.

 Interim Revision Announcement
2 Cefdinir Official September 1, 2014

Table 1 (Continued) Table 2

Time Solution E Solution F Relative Relative Acceptance
(min) (%) (%) Retention Response Criteria,
38 95 5 Name Time Factor NMT (%)
58 95 5 Thiazolylacetyl
glycine oximea . 0.10 1.0 0.5
System suitability stock solution 1: 40 µg/mL of USP Thiazolylacetyl
Cefdinir Related Compound A RS in Solution C glycine oxime
System suitability stock solution 2: 40 µg/mL of USP acetalb 0.13 1.0 0.5
Cefdinir Related Compound B RS in Solution C
.

Cefdinir sulfoxidec 0.36 1.0 0.2

System suitability solution: Transfer 37.5 mg of USP
.

Cefdinir thiazine
Cefdinir RS to a 25-mL volumetric flask. Add about analogd 0.46 0.68 0.7
10 mL of Buffer. Add 5.0 mL each of System suitability .

stock solution 1 and System suitability stock solution 2, 3-Methyl cefdinire . 0.75 1.0 0.7
and dilute with Solution C to volume. Cefdinir impurity 1f . 0.77 1.0 0.3
Standard stock solution: 750 µg/mL of USP Cefdinir Cefdinir related
RS in Buffer compound A
Standard solution: 15 µg/mL of USP Cefdinir RS, from (cefdinir open ring
the Standard stock solution, in Solution C lactone a)g,h . . . 0.85 0.65
Sample solution: Transfer an equivalent to 300 mg of Cefdinir related
cefdinir from Capsule contents (NLT 20) to a 200-mL compound A
volumetric flask. Dissolve in 30 mL of Buffer, and dilute (cefdinir open ring
with Solution C to volume to obtain a solution with a lactone b)g,h 0.94 0.65
nominal concentration of about 1.5 mg/mL of cefdinir. 2.5
. . .

Cefdinir related
Chromatographic system compound A
(See Chromatography 〈621〉, System Suitability.) (cefdinir open ring
Mode: LC lactone c)g,h 1.11 0.65
Detector: UV 254 nm
. . .

Cefdinir related
Column: 4.6-mm × 15-cm; 5-µm packing L1 compound A
Temperatures (cefdinir open ring
Autosampler: 4° lactone d)g,h 1.14 0.65
Column: 40° . . .

Flow rate: 1 mL/min 7S-Cefdiniri . 1.18 1.0 0.2

Injection volume: 10 µL Cefdinir lactonej . 1.23 1.0 1.0
System suitability Cefdinir related
Samples: System suitability solution and Standard compound Bk . 1.28 1.0 0.2
solution Cefdinir isoxazole
Suitability requirements analogl 1.37 0.72 0.5
Resolution: NLT 1.5 between cefdinir and the third
.

a N-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetyl]glycine.
peak of USP Cefdinir Related Compound A RS, Sys- .

b (Z)-2-(2-Aminothiazol-4-yl)-N-(2,2-dihydroxyethyl)-2-(hydroxyimi-
tem suitability solution no)acetamide.
.

Tailing factor: NMT 1.5 for cefdinir related com- c (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-5,8-

pound B, System suitability solution
.

dioxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Relative standard deviation: NMT 2.0% for the d (R,Z)-2-{(R)-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimi-
.

cefdinir peak, Standard solution no)acetamido](carboxy)methyl}-5-ethylidene-5,6-dihydro-2H-1,3-thiazine-

Analysis 4-carboxylic acid.
e (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-
Samples: Standard solution and Sample solution .

methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Calculate the percentage of each impurity in the por- f Cefdinir impurity 1, cefdinir impurity 2, and cefdinir impurity 3 are un-
tion of Capsules taken:
.

identified impurities.
g Cefdinir related compound A is a mixture of four isomers labeled
Result = (rU/rS) × (CS/CU) × (100/F)
.

cefdinir open ring lactones a, b, c, and d. The sum of the values is

reported. The limit for the sum of the four isomers is 2.5%.
rU = peak response of each impurity from the h 2(R)-2-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-2-
.

Sample solution [(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-

2-yl]acetic acid.
rS = peak response from the Standard solution i (6R,7S)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-
CS = concentration of the Standard solution .

oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
(mg/mL) j (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-((3RS,5aR,6R)-3-methyl-
CU = nominal concentration of cefdinir in the
.

1,7-dioxo-1,3,4,5a,6,7-hexahydroazeto[2,1-b]furo[3,4-d][1,3]thiazin-6-
Sample solution (mg/mL) yl)acetamide.
F = relative response factor (see Table 2) k (6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-8-oxo-3-vinyl-5-thia-1-

Acceptance criteria: See Table 2. •The reporting

.

azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
l (6R,7R)-7-(4-Hydroxyisoxazole-3-carboxamido)-8-oxo-3-vinyl-5-thia-1-
.

threshold is 0.1%. .

azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
m (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2-oxoacetamido]-8-oxo-3-vinyl-5-
.

thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
n (6R,7R)-7-[(E)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-
.

oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
o Cefdinir decarboxy open ring lactone is a mixture of two isomers la-
.

beled cefdinir decarboxy open ring lactone a and b. The sum of the
values is reported. The limit for the sum of the two isomers is 1.0%.
p (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-{[(2RS,5RS)-5-methyl-7-
.

oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]methyl}acetamide.

2014 The United States Pharmacopeial Convention All Rights Reserved.

Interim Revision Announcement
Official September 1, 2014 Cefdinir 3

Table 2 (Continued)
Relative Relative Acceptance
Retention Response Criteria,
Name Time Factor NMT (%)
Cefdinir impurity 2f . 1.44 1.0 0.5
Cefdinir glyoxalic
analogm . 1.49 1.0 0.2
E-Cefdinirn . 1.51 1.0 1.2
Cefdinir decarboxy
open ring lactone
ao,p 1.62 1.0
1.0
. . .

Cefdinir decarboxy
open ring lactone
bo,p . . . 1.64 1.0
Cefdinir impurity 3f . 1.82 1.0 0.2
Individual unidenti-
—
fied impurities 1.0 0.2
Total impurities — — 5.0
a N-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetyl]glycine.
.

b (Z)-2-(2-Aminothiazol-4-yl)-N-(2,2-dihydroxyethyl)-2-(hydroxyimi-
.

no)acetamide.
c (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-5,8-
.

dioxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
d (R,Z)-2-{(R)-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimi-
.

no)acetamido](carboxy)methyl}-5-ethylidene-5,6-dihydro-2H-1,3-thiazine-
4-carboxylic acid.
e (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-
.

methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
f Cefdinir impurity 1, cefdinir impurity 2, and cefdinir impurity 3 are un-
.

identified impurities.
g Cefdinir related compound A is a mixture of four isomers labeled
.

cefdinir open ring lactones a, b, c, and d. The sum of the values is

reported. The limit for the sum of the four isomers is 2.5%.
h 2(R)-2-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-2-
.

[(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-
2-yl]acetic acid.
i (6R,7S)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-
.

oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
j (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-((3RS,5aR,6R)-3-methyl-
.

1,7-dioxo-1,3,4,5a,6,7-hexahydroazeto[2,1-b]furo[3,4-d][1,3]thiazin-6-
yl)acetamide.
k (6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-8-oxo-3-vinyl-5-thia-1-
.

azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
l (6R,7R)-7-(4-Hydroxyisoxazole-3-carboxamido)-8-oxo-3-vinyl-5-thia-1-
.

azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
m (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2-oxoacetamido]-8-oxo-3-vinyl-5-
.

thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
n (6R,7R)-7-[(E)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-
.

oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
o Cefdinir decarboxy open ring lactone is a mixture of two isomers la-
.

beled cefdinir decarboxy open ring lactone a and b. The sum of the
values is reported. The limit for the sum of the two isomers is 1.0%.
p (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-{[(2RS,5RS)-5-methyl-7-
.

oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]methyl}acetamide.

• (IRA 1-Sep-2014)
ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight, light-resistant
containers, and store at controlled room temperature.
• USP REFERENCE STANDARDS 〈11〉
USP Cefdinir RS
USP Cefdinir Related Compound A RS
(2R)-2-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimi-
no)acetamido]-2-[(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-
tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]acetic acid
(three other stereoisomers are also present in this RS).
C14H15N5O6S2 413.43
USP Cefdinir Related Compound B RS
(6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-8-oxo-
3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox-
ylic acid.
C14H13N4O4S2 365.41

2014 The United States Pharmacopeial Convention All Rights Reserved.